A new cohort study found that the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors may be associated with a significantly reduced risk of lupus nephritis, dialysis, kidney transplant, heart failure, and all-cause mortality in patients with systemic lupus erythematosus and type 2 diabetes.

The study, published in JAMA Network Open, investigators analyzed the data of 3,550 matched patients using the TriNetX clinical data platform.The investigators identified patients with lupus and type 2 diabetes from January 1, 2015, to December 31, 2022, using the U.S. Collaborative Network of the TriNetX platform. The patients were categorized into SGLT2 inhibitor users and nonusers with 1:1 propensity score matching. The final analysis included 1,775 matched pairs. 

Key baseline characteristics after matching included:

• Mean (SD) age = 56.8 (11.6) years
• Female = 84.8%
• White = 55.8%
• Black = 25.5%

Outcomes were assessed using ICD-10-CM codes and included lupus nephritis, dialysis, kidney transplant, heart failure, and all-cause mortality. Kaplan-Meier analysis and Cox proportional hazards regression were used to calculate 5-year adjusted hazard ratios.

SGLT2 inhibitor users had a 45% lower risk of developing lupus nephritis (adjusted hazard ratio [HR] = 0.55, 95% confidence interval [CI] = 0.40–0.77), 71% lower risk of requiring dialysis (adjusted HR = 0.29, 95% CI = 0.17–0.48), 86% lower risk of kidney transplant (adjusted HR = 0.14, 95% CI = 0.03–0.62), 35% lower risk of heart failure (adjusted HR = 0.65, 95% CI = 0.53–0.78), and 65% lower risk of all-cause mortality (adjusted HR = 0.35, 95% CI = 0.26–0.47) compared with nonusers over 5 years of follow-up.

The protective association of SGLT2 inhibitors remained consistent across multiple subgroup and sensitivity analyses:

• Patients with HbA1c ≥ 7%: lower risk of lupus nephritis (adjusted HR = 0.94, 95% CI = 0.53–1.65), dialysis, heart failure, and mortality
• Patients with creatinine < 1.5 mg/dL: lower risk of lupus nephritis (adjusted HR = 0.80, 95% CI = 0.49–1.29), dialysis, heart failure, and mortality
• Patients with eGFR < 60 mL/min/1.73 m2: lower risk of lupus nephritis (adjusted HR = 0.81, 95% CI = 0.49–1.34), dialysis, heart failure, and mortality
• Patients with chronic kidney disease: lower risk of lupus nephritis (adjusted HR = 0.65, 95% CI = 0.33–1.27), dialysis, heart failure, and mortality.

Compared with sulfonylurea users, SGLT2 inhibitor users had a lower risk of all outcomes. Compared with DPP-4 inhibitor users, SGLT2 inhibitor users had a lower risk of dialysis, kidney transplant, heart failure, and mortality.

The patients with at least two SGLT2 inhibitor prescriptions had a lower risk of all outcomes compared to nonusers.

The investigators noted several limitations of the study, including potential selection bias from hospital-based data, a lack of biopsy confirmation for lupus nephritis diagnosis, and possible unmeasured confounding factors. They emphasized that the results indicated associations rather than causal relationships.

This large cohort study suggested that SGLT2 inhibitors may provide nephroprotective and cardioprotective benefits in patients with both lupus and type 2 diabetes. The investigators called for prospective randomized controlled trials to confirm these findings.

The authors declared having no competing interests.